EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of steroidogenic acute regulatory protein (StAR) messenger ribonucleic acid (mRNA) in human ovary and cultured proliferating granulosa-lutein cells, theca interna cells, and luteinized granulosa cells was examined. The StAR transcripts were restricted in situ to theca of preovulatory follicles and luteinized granulosa and thecal cells of the corpus luteum. The cyclic nucleotide analog, 8-bromo-cAMP (8-Br-cAMP), increased StAR mRNA in all cell types studied by a process requiring on-going RNA and protein synthesis. Phorbol myristate acetate prevented the stimulatory effects of 8-Br-cAMP. In proliferating granulosa-lutein cells, 8-Br-cAMP increased StAR gene transcription and did not significantly affect StAR mRNA stability. Forskolin treatment was also found to increase the expression of a human StAR proximal promoter-luciferase fusion gene transfected into the proliferating granulosa-lutein cells. We conclude that 1) the StAR gene is expressed in the most steroidogenic compartments of the human ovary; 2) induction of StAR gene transcription by cAMP, produced in response to the LH surge, accounts for the appearance of StAR transcripts in luteinized granulosa cells; and 3) the effects of cAMP are antagonized by activators of protein kinase C.
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PMID:Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. 892 70

Ligand- and second messenger-regulated expression of the gene for steroidogenic acute regulatory protein (StAR) was evaluated in luteinized porcine granulosa cells. For comparison, cytochrome P450 side-chain cleavage (P450scc) was examined. Northern hybridization with homologous cDNA probes demonstrated three StAR mRNA species, of 2.7, 1.6, and 0.8 kilobases (kb), with the smallest variably present, and a single P450scc band at 1.9 kb. FSH elevated both STAR and P450scc messages in a dose-dependent manner over 6 h and continually stimulated both over 24 h (p < 0.001). STAR message induction depended on transcription, as did that of P450scc. Over 6 h, actinomycin D eliminated constitutive StAR message and reduced that of P450scc by two thirds, indicating briefer persistence of StAR. Pretreatment with cycloheximide prevented FSH induction of StAR and P450scc mRNA, implicating intermediate protein synthesis in expression of both genes. Dibutyryl cAMP caused time-dependent increases in StAR and P450 mRNAs over 24 h (p < 0.001), indicating the importance of the protein kinase A (PKA) pathway in their gene expression. Activation of the protein kinase C (PKC) pathway by a phorbol ester eliminated FSH induction of STAR mRNA increases (p < 0.01) while only reducing P450scc induction (p < 0.05). Thus, StAR gene expression, as reflected in mRNA abundance, is regulated by FSH via the PKA pathway and is dependent on transcription and translation. Conversely, the PKC pathway inhibits induction of these important steroid synthetic genes in luteinized granulosa cells.
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PMID:Follicle-stimulating hormone and intracellular second messengers regulate steroidogenic acute regulatory protein messenger ribonucleic acid in luteinized porcine granulosa cells. 928 5

Steroidogenic tissue can respond almost immediately to a stimulatory hormonal stimuli. Recent findings are shedding light on the molecular and cellular mechanisms that are used to synthesize and export steroid hormones in the acute phase of stimulation. In addition to utilising the cAMP intracellular messenger system to convey a stimulatory message, steroidogenic cells may employ the protein kinase C, arachidonic acid, tyrosine phosphate and nitrous oxide systems. It has been proposed that cholesterol laden vesicles travel along a network of intermediate filaments to reach the mitochondria. Cholesterol may then translocate from the outer mitochondrial membrane to the inner via sites of contact between the two membranes. These contact sites may be composed of protein bridges which include the constituents, porin, the benzodiazepine receptor and GTP binding proteins. Cholesterol is transported through the contact sites to the inner membrane and on reaching cytochrome P450 side chain cleavage (P450scc), cholesterol is converted to pregnenolone. Pregnenolone is in turn converted to a range of steroid hormones via enzyme casades. GTP binding proteins may regulate the contact site between the inner and outer membranes and thereby modulate cholesterol flux to P450scc. In the adrenal and gonads the rate that cholesterol traverses the contact point to reach the inner membrane is accelerated by the steroidogenic acute regulatory protein. Newly synthesized steroid hormones are transported to the cell periphery for export via a mechanism that may utilise an ion exchange protein.
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PMID:Molecular and cellular mechanisms used in the acute phase of stimulated steroidogenesis. 950 34

Atrial natriuretic peptide (ANP) is a cardiac hormone that inhibits aldosterone secretion induced by all physiologic agonists. The purpose of this study is to explore ANP-induced changes in the phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) and the steroidogenic acute regulatory protein (StAR), in AngII or K(+)-stimulated glomerulosa cells. The data show that ANP completely inhibits the phosphorylation of MARCKS and partially inhibits that of StAR in cells stimulated with K(+). ANP also partially inhibits MARCKS phosphorylation but does not affect StAR phosphorylation in cells stimulated with AngII. These effects appear to be cGMP-independent and at least partially dependent on inhibition of protein kinase C (PKC). To our knowledge, this is the first report of ANP modulating either MARCKS or StAR phosphorylation in [(32)P]-labeled cells. The data also support the hypothesis that ANP inhibits aldosterone secretion acting as a step involved in cholesterol transport to the mitochondria.
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PMID:ANPs effect on MARCKS and StAR phosphorylation in agonist-stimulated glomerulosa cells. 1137 22

After the luteinizing hormone (LH) surge, the cells that remain from the ovulated follicle undergo a process of differentiation termed luteinization. Two key features of the cells after luteinization are the capacity for tremendous production of progesterone [10(16) molecules of progesterone per (min/(g of CL))] and the capacity to undergo regression or death of the cells at the appropriate time. There are two steroidogenic cell types, the small and large luteal cells that are regulated by different mechanisms. In small luteal cells, production of progesterone is stimulated by LH through the protein kinase A (PKA) pathway. The large luteal cells of ruminants produce large quantities of progesterone that is independent of LH stimulation. Although luteotrophins clearly regulate luteal function, much of luteal progesterone production in some species appears to be constitutive, consistent with the autonomous aspects of the large luteal cell. The key regulated step in luteal progesterone production appears to be regulation of transport of cholesterol to the inner mitochondrial membrane apparently mediated by the steroidogenic acute regulatory protein (StAR). In addition, our recent research indicates that PKA is tonically active in large luteal cells and this may be responsible for the high, relatively autonomous nature of luteal progesterone production. Regression of the corpus luteum (CL) in many species is initiated by prostaglandin (PG) F2alpha secreted from the uterus. Luteal cells also have the capacity for production of PGF2alpha. Luteal PGF2alpha production can be regulated by a variety of substances including inhibition by progesterone and stimulation by cytokines. We have also characterized a positive feedback pathway in ruminant and porcine CL in which small amounts of uterine PGF(2alpha) stimulate intraluteal production of PGF2alpha due to induction of the cycloxygenase-2 (Cox-2) enzyme in large luteal cells. This positive feedback pathway is only present in CL that has acquired the capacity for luteal regression ( approximately day 7 in cow, approximately day 13 in pig). Regulation by protein kinase C (PKC) of transcriptional factors interacting with an E-box in the 5' flanking region of the Cox-2 gene is the critical regulatory element involved in this positive feedback pathway. Thus, luteinization in some species appears to change specific gene transcription such that progesterone production becomes relatively independent of acute luteotrophic regulation and intraluteal PGF2alpha synthesis is induced by the second messenger pathways that are activated by PGF2alpha.
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PMID:Regulation of progesterone and prostaglandin F2alpha production in the CL. 1204 20

The present studies were conducted to address cellular mechanisms responsible for regulating steroidogenic acute regulatory protein (StAR) expression and progesterone synthesis at maturational stages corresponding to both the time of hen follicle selection, as well as before and after the LH surge in preovulatory follicle granulosa cells. A recently published report has established that mitogen-activated protein (MAP) kinase signaling induced by transforming growth factor alpha (TGFalpha) treatment blocks FSH-induced differentiation and StAR expression in cultured hen granulosa cells, whereas inhibitors of MAP kinase signaling enhance FSH-induced differentiation. The present in vitro studies demonstrate that in addition to MAP kinase signaling, activation of protein kinase C (PKC) blocks both FSH-induced StAR expression and the initiation of progesterone production in prehierarchal follicle granulosa cells, whereas the pharmacologic inhibitor of PKC, GF109203X, potentiates FSH-induced StAR expression and, as a consequence, the initiation of progesterone synthesis. Moreover, we demonstrate in granulosa cells collected from preovulatory follicles that although an acute increase in progesterone production in response to LH treatment requires rapid transcription and translation of StAR, the magnitude of progesterone production is rate-limited by one or more factors other than StAR (e.g., the P450 cholesterol side-chain enzyme). Finally, the rapid turnover of StAR protein, such as occurs following the withdrawal of LH, provides an additional mechanism for the tight regulation of progesterone production that occurs during the hen ovulatory cycle, and explains the rapid loss of steroidogenesis in the postovulatory follicle. In summary, data reported herein support the proposal that paracrine/autocrine factors (including but not necessarily limited to TGFalpha) prevent premature expression of StAR in prehierarchal follicle granulosa cells by more than one receptor-mediated signaling pathway. Furthermore, subsequent to follicle selection into the preovulatory hierarchy, StAR transcription and translation is necessary but not sufficient for the full potentiation of the preovulatory surge of serum progesterone.
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PMID:Relationship between steroidogenic acute regulatory protein expression and progesterone production in hen granulosa cells during follicle development. 1229 50

Angiotensin II- and K+-stimulated aldosterone production in the adrenocortical glomerulosa cells requires induction of the steroidogenic acute regulatory protein (StAR). While both agents activate Ca2+ signaling, the mechanisms leading to aldosterone synthesis are distinct, and the angiotensin II response cannot be mimicked by K+. We previously reported that StAR mRNA levels and promoter-reporter gene activity in transiently transfected H295R human adrenocortical cells were stimulated by angiotensin II but not by K+ treatment. The current study focused on identifying signaling pathways activated by angiotensin II that contribute to StAR transcriptional activation. We show that the angiotensin II-stimulated transcriptional activation of StAR was dependent upon influx of external calcium and requires protein kinase C activation. Furthermore we describe for the first time that the Janus tyrosine kinase family member, JAK2, was activated by angiotensin II treatment of H295R cells. Treatment of the cells with AG490, a selective inhibitor of JAK2, blocked JAK2 activation and StAR reporter gene activity and inhibited steroid production. Taken together these studies describe a novel pathway controlling StAR expression and steroidogenesis in adrenocortical cells.
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PMID:Janus kinase 2 and calcium are required for angiotensin II-dependent activation of steroidogenic acute regulatory protein transcription in H295R human adrenocortical cells. 1456 54

We studied the involvement of the ERK cascade in human chorionic gonadotropin (hCG)-induced steroidogenesis by primary cultures of immature rat Leydig cells. Our findings indicate that protein kinase A and protein kinase C function as upstream kinases in connection with transduction of the signal from the gonadotropin receptor to the ERK cascade. These MAPKs enhance the stimulatory effects of hCG on the de novo synthesis of the steroidogenic acute regulatory protein and the activity of protein phosphatase 2A, which are associated with increased androgen production by the Leydig cell. Specific inhibition of ERK1/2 by Uo126 suppressed all of these cellular responses to hCG. In contrast, steroidogenesis from 22OHC (a cell-permeable form of cholesterol) is not inhibited by Uo126, suggesting that cholesterol delivery to mitochondria is being affected by this compound. We propose that the ERK cascade is an important part of the signal transduction pathway involved in the rapid hormonal responses of Leydig cells to trophic hormones. In hCG-activated Leydig cells, these MAPKs may play a role in controlling the biosynthesis of the steroidogenic acute regulatory protein as well as regulating protein phosphatase 2A activity, thereby governing cholesterol transport across the mitochondrial membrane.
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PMID:Extracellular signal-regulated kinases are involved in the acute activation of steroidogenesis in immature rat Leydig cells by human chorionic gonadotropin. 1524 88

Angiotensin II (Ang II)-stimulated aldosterone production in adrenocortical glomerulosa cells requires de novo expression of the steroidogenic acute regulatory protein (StAR). We previously reported that StAR mRNA levels and promoter-reporter gene activity in transiently transfected H295R human adrenocortical cells were stimulated by Ang II and the goals for the current study were to identify signaling pathways activated by Ang II that contribute to StAR transcriptional activation. Using StAR promoter-reporter gene activity and pharmacological inhibition of signaling pathways, we have shown that Ang II-stimulated StAR transcription in H295R cells is dependent upon both influx of external Ca2+ and tyrosine kinase signaling and is enhanced by protein kinase C and mitogen-activated protein kinase (ERK1/2) activation. In particular, Janus tyrosine kinase-2 (Jak2) activation was increased with Ang-II treatment of H295R cells and the select Jak2 inhibitor, AG490, blocked Ang II-dependent Jak2 activation, StAR reporter gene activity, and steroid production. The Ang II-dependent, but not (Bu)2cAMP-dependent, induction of StAR mRNA was also blocked by AG490 and shown to be sensitive to cycloheximide treatment. Together our data support Jak2 as a novel pathway in the Ang II-dependent activation of StAR expression and steroidogenesis in adrenocortical cells and indicate a requirement for ongoing protein synthesis in Ang II-mediated StAR transcription.
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PMID:Janus kinase 2 signaling in the angiotensin II-dependent activation of StAR expression. 1566 12

Steroid hormone biosynthesis in steroidogenic cells is regulated through trophic hormone activation of protein kinase A (PKA) signaling pathways. However, many examples of the regulation of steroid synthesis via pathways other than the PKA pathway have been documented. In some cases these pathways act independently of PKA activation whereas in other cases, they act synergistically with it. The current understanding of additional signaling pathways and factors, such as the protein kinase C pathway, arachidonic acid metabolites, growth factors, chloride ion, the calcium messenger system, and others capable of regulating/modulating steroid hormone biosynthesis, and in many cases steroidogenic acute regulatory protein expression, are discussed in this review.
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PMID:Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. 1583 19

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